Claims for Patent: 9,758,561

Summary for Patent: 9,758,561

Title:	Dual GLP-1/glucagon receptor agonists derived from exendin-4
Abstract:	The present invention relates to dual GLP-1/glucagon receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.
Inventor(s):	Bossart; Martin (Frankfurt am Main, DE), Elvert; Ralf (Frankfurt am Main, DE), Evers; Andreas (Frankfurt am Main, DE), Haack; Torsten (Frankfurt am Main, DE), Stengelin; Siegfried (Frankfurt am Main, DE), Wagner; Michael (Frankfurt am Main, DE), Kadereit; Dieter (Frankfurt am Main, DE)
Assignee:	SANOFI (Paris, FR)
Application Number:	14/679,770
Patent Claims:	1. A peptidic compound having the formula (I): H.sub.2N-His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-Glu-Gl- u-Ala-X19-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Aib-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-- Pro-Pro-Pro-Ser-R.sup.1 (I) or a salt or solvate thereof, wherein X2 is an amino acid residue selected from the group consisting of D-Ser and Ser, X3 is an amino acid residue selected from the group consisting of Gin and His, X14 is an amino acid residue with a functionalized --NH.sub.2 side chain group selected from the group consisting of Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is functionalized by --Z--C(O)--R.sup.5, wherein Z is a linker comprising 1-5 amino acid linker groups selected from the group consisting of .gamma.-glutamate (.gamma.E) and AEEAc and combinations thereof in all stereoisomeric forms, R.sup.5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from the group consisting of N and O, X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser, X29 is an amino acid residue selected from the group consisting of Thr, D-Ala, and Gly, and R.sup.1 is NH.sub.2 or OH. 2. The compound or salt or solvate thereof of claim 1, wherein R.sup.1 is NH.sub.2. 3. The compound or salt or solvate thereof of claim 1, wherein the peptidic compound has a relative activity of at least 0.1% compared to that of natural glucagon at the glucagon receptor. 4. The compound or salt or solvate thereof of claim 1, wherein the peptidic compound exhibits a relative activity of at least 0.1% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor. 5. The compound or salt or solvate thereof of claim 1, wherein X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group --Z--C(O)R.sup.5, wherein Z is a group selected from the group consisting of .gamma.E, .gamma.E-.gamma.E, AEEAc-AEEAc-.gamma.E, and AEEAc-AEEAc-AEEAc, and R.sup.5 is a group selected from the group consisting of pentadecanyl, heptadecanyl, and 16-carboxy hexadecanyl. 6. The compound or salt or solvate thereof of claim 5, wherein X14 is Lys wherein the --NH.sub.2 side chain group is functionalized with a group --Z--C(O)R.sup.5, wherein Z is a group selected from the group consisting of .gamma.E, .gamma.E-.gamma.E, AEEAc-AEEAc-.gamma.E, and AEEAc-AEEAc-AEEAc, and R.sup.5 is a group selected from the group consisting of pentadecanyl and heptadecanyl. 7. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser, X29 is an amino acid residue selected from the group consisting of Thr, D-Ala, and Gly, and R.sup.1 is NH.sub.2. 8. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is Ala, X28 is an amino acid residue selected from the group consisting of Ala and Lys, X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and R.sup.1 is NH.sub.2. 9. The compound or salt or solvate thereof of claim 1, wherein X2 is an amino acid residue selected from the group consisting of D-Ser and Ser, X3 is Gln, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser, X29 is an amino acid residue selected from the group consisting of Thr, D-Ala, and Gly, and R.sup.1 is NH.sub.2. 10. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the groups consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , X15 is Glu, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is an amino acid residue selected from the group consisting of Ala and Lys, X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and R.sup.1 is NH.sub.2. 11. The compound or salt or solvate thereof of claim 1, wherein X2 is an amino acid residue selected from the group consisting of D-Ser and Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, X15 is Asp, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser, X29 is an amino acid residue selected from the group consisting of Thr, D-Ala, and Gly, and R.sup.1 is NH.sub.2. 12. The compound or salt or solvate thereof of claim 1, wherein X2 is an amino acid residue selected from the group consisting of D-Ser and Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is Ala, X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser, X29 is an amino acid residue selected from Thr, D-Ala, and Gly, and R.sup.1 is NH.sub.2. 13. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is Gln, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is Val, X28 is Ala, X29 is Gly, and R.sup.1 is NH.sub.2. 14. The compound or salt or solvate thereof of claim 1, wherein X2 is an amino acid residue selected from the group consisting of D-Ser and Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is Ala, X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and R.sup.1 is NH.sub.2. 15. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is Gln, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by the group (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl, X15 is Asp, X19 is Ala, X28 is Ser, X29 is an amino acid residue selected from the group consisting of Thr and Gly, and R.sup.1 is NH.sub.2. 16. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is Ala, X28 is Lys, X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and R.sup.1 is NH.sub.2. 17. The compound or salt or solvate thereof of claim 1, wherein X2 is an amino acid residue selected from the group consisting of D-Ser and Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is an amino acid residue selected from the group consisting of Ala and Val, X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser, X29 is Gly, and R.sup.1 is NH.sub.2. 18. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is an amino acid residue selected from the group consisting of Gln and His, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , X15 is an amino acid residue selected from the group consisting of Glu and Asp, X19 is Ala, X28 is an amino acid residue selected from the group consisting of Ala and Lys, X29 is D-Ala, and R.sup.1 is NH.sub.2. 19. The compound or salt or solvate thereof of claim 1, wherein X2 is D-Ser, X3 is Gln, X14 is Lys wherein the --NH.sub.2 side chain group is functionalized by the group (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , X15 is Asp, X19 is Ala, X28 is an amino acid residue selected from the group consisting of Ala and Ser, X29 is an amino acid residue selected from the group consisting of Gly and D-Ala, and R.sup.1 is NH.sub.2. 20. The compound of claim 1, selected from any one of the compounds of SEQ ID NOs: 6-27, or a salt or solvate thereof. 21. The compound of claim 20, selected from any one of the compounds of SEQ ID NOs: 6-22 and 24-27, or a salt or solvate thereof. 22. The compound, salt or solvate of claim 1, consisting of the amino acid sequence of SEQ ID NO: 6, or a salt or solvate thereof. 23. The compound, salt or solvate of claim 1, consisting of the amino acid sequence of SEQ ID NO: 7, or a salt or solvate thereof. 24. The compound, salt or solvate of claim 1, consisting of the amino acid sequence of SEQ ID NO: 9, or a salt or solvate thereof. 25. A solvate of a compound of claim 1. 26. A hydrate of a compound of claim 1. 27. A pharmaceutical composition comprising one or more compounds of claim 1 or a salt or solvate thereof as an active ingredient and at least one pharmaceutically acceptable carrier. 28. The pharmaceutical composition of claim 27, further comprising at least one additional therapeutically active agent, wherein the additional therapeutically active agent is selected from the group consisting of: insulin and insulin derivatives selected from the group consisting of: insulin glargine, insulin glusiline, insulin detemir, insulin lispro, insulin degludec, insulin aspart, basal insulin and analogues thereof, pegylated insulin, recombinant human insulin, polysialated insulins, long-acting insulin, NN1045, insulin in combination with pramlintide, PE0139, fast-acting and short-acting insulins, insulin hydrogel, oral insulin, inhalable insulin, transdermal insulin and sublingual insulin, and insulin derivatives which are bonded to albumin or another protein by a bifunctional linker; GLP-1, GLP-1 analogues, and GLP-1 receptor agonists selected from the group consisting of: lixisenatide, exenatide, exendin-4, ITCA 650, AC-2993, liraglutide, semaglutide, taspoglutide, albiglutide, dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide, HM-11260C, CM-3, ORMD-0901, NN-9924, NN-9926, NN-9927, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034, MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, xtenylated exenatide, xtenylated glucagon, and polymer bound derivatives thereof; dual GLP-1/GIP receptor agonists; dual GLP-1/glucagon receptor agonists; protein YY.sub.3-36 (PYY3-36); pancreatic polypeptide; glucagon receptor agonists; GIP receptor agonists or antagonists; ghrelin receptor antagonists or inverse agonists; xenin; dipeptidyl peptidase IV (DPP-IV) inhibitors; sodium glucose cotransporter 2 (SGLT2) inhibitors; dual SGLT2/SGLT1 inhibitors; biguanides; thiazolidinediones; dual peroxisome proliferator-activated receptor (PPAR) agonists; sulfonylureas; meglitinides; alpha-glucosidase inhibitors; amylin; pramlintide; G protein-coupled receptor 119 (GPR119) agonists; GPR40 agonists; GPR120 agonists; GPR142 agonists; systemic or low-absorbable transmembrane G protein-coupled receptor 5 (TGR5) agonists; bromocriptine mesylate; inhibitors of 11-beta-hydroxysteroid dehydrogenase (HSD); activators of glucokinase; inhibitors of diacylglycerol acyltransferase (DGAT); inhibitors of protein tyrosinephosphatase 1; inhibitors of glucose-6-phosphatase; inhibitors of fructose-1,6-bisphosphatase; inhibitors of glycogen phosphorylase; inhibitors of phosphoenol pyruvate carboxykinase; inhibitors of glycogen synthase kinase; inhibitors of pyruvate dehydrogenase kinase; alpha2-antagonists; C-C motif receptor (CCR-2) antagonists; modulators of glucose transporter-4; somatostatin receptor 3 agonists; 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitors; fibrates; nicotinic acid and derivatives thereof; nicotinic acid receptor 1 agonists; PPAR-alpha, gamma, or alpha/gamma agonists or modulators; PPAR-delta agonists; acyl-CoA cholesterol acyltransferase (ACAT) inhibitors; cholesterol absorption inhibitors; bile acid-binding substances; ileal bile acid transporter (IBAT) inhibitors; microsomal triglyceride transfer protein (MTP) inhibitors; modulators of proprotein convertase subtilisin/kinexin type 9 (PCSK9); low-density lipoprotein (LDL) receptor up-regulators by liver selective thyroid hormone receptor .beta. agonists; high-density lipoprotein (HDL)-raising compounds; lipid metabolism modulators; phospholipase A2 (PLA2) inhibitors; apolipoprotein A1 (ApoA-1) enhancers; thyroid hormone receptor agonists; cholesterol synthesis inhibitors; and omega-3 fatty acids and derivatives thereof; substances for the treatment of obesity selected from the group consisting of: sibutramine, tesofensine, tetrahydrolipstatin, cannabinoid-1 (CB-1) receptor antagonists, melanin-concentrating hormone-1 (MCH-1) antagonists, melanocortin 4 (MC4) receptor agonists or partial agonists, neuropeptide Y5 (NPY5) or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, combinations of bupropione/naltrexone, combinations of bupropione/zonisamide, combinations of bupropione/phentermine, combinations of pramlintide/metreleptin, and combinations of phentermine/topiramate; lipase inhibitors; angiogenesis inhibitors; H3 antagonists; Agouti-related protein (AgRP) inhibitors; triple monoamine uptake inhibitors; methionine aminopeptidase type 2 (MetAP2) inhibitors; nasal formulation of the calcium channel blocker diltiazem; antisense molecules against production of fibroblast growth factor receptor 4; and prohibitin targeting peptide-1; and drugs for influencing high blood pressure, chronic heart failure, or atherosclerosis selected from the groups consisting of: angiotensin II receptor antagonists, angiotensin-converting-enzyme (ACE) inhibitors, endothelin-converting-enzyme (ECE) inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, and thrombocyte aggregation inhibitors. 29. A method for the treatment of hyperglycemia, type 1 diabetes, type 2 diabetes, obesity or any combination of these individual disease components, the method comprising administering to a patient in need of such treatment an effective amount of one or more compounds, salts or solvates of claim 1. 30. The method of claim 29, for the treatment of hyperglycemia or type 2 diabetes. 31. A method for the simultaneous treatment of diabetes and obesity which comprises administering to a patient in need of such treatment an effective amount of one or more compounds, salts or solvates of claim 1. 32. A method for the treatment of hyperglycemia, type 2 diabetes, type 1 diabetes, or obesity or any combination of these individual disease components, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition of claim 27. 33. The method of claim 32, for the treatment of hyperglycemia or type 2 diabetes. 34. A method for the simultaneous treatment of diabetes and obesity, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition of claim 27.

Details for Patent 9,758,561

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	10/28/1982		2034-04-07
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	12/29/2015		2034-04-07
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	08/06/1998		2034-04-07
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	03/31/1994		2034-04-07
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	05/25/2018		2034-04-07
Novo Nordisk Inc.	NOVOLIN R	insulin human	Injection	019938	06/25/1991		2034-04-07